Development of capsid- and genome-modified optimized AAVrh74 vectors for muscle gene therapy.
Development of capsid- and genome-modified optimized AAVrh74 vectors for muscle gene therapy.
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用于肌肉基因治疗的衣壳和基因组修饰的优化AAVrh74载体的开发。
DOI：
10.1016/j.omtm.2023.101147
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发表时间：
2023-12-14
期刊：
影响因子：
--
通讯作者：
Srivastava, Arun
中科院分区：
文献类型：
--
作者：
Shoti, Jakob;Qing, Keyun;Keeler, Geoffrey D.;Duan, Dongsheng;Byrne, Barry J.;Srivastava, Arun
由天然存在的衣壳和基因组组成的第一代腺相关病毒（AAV）载体虽然在某些情况下有效，但不太可能是人类基因治疗的最佳选择。在四个单独的临床试验中使用第一代两种不同的AAV血清型载体（AAV9和AAVrh74）在杜氏肌营养不良症患者中未能有效，尽管在使用AAVrh74载体的患者亚组中观察到一些功效，导致美国食品和药物管理局批准（Elevidys）。在使用第一代AAV9载体的两项试验中，观察到了几种严重的不良事件，包括一项试验中的患者死亡，以及最近的N-of-1临床试验中的第二名患者死亡。在使用第一代AAVrh74载体的第四次试验中，还观察到肌炎和心肌炎。在这里，我们报告了衣壳和基因组修饰的优化AAVrh74载体在体外转导原代人骨骼肌细胞和在小鼠模型中全身给药后体内转导所有主要肌肉组织中显著更有效。优化的AAVrh74载体的可用性有望在人类肌肉疾病的潜在基因治疗中安全有效。第一代重组腺相关病毒（AAV）载体由天然存在的衣壳和基因组组成，尽管在某些情况下有效，但考虑到几名患者的严重不良事件和死亡，不是最佳的。本文所述的优化的AAV载体有望在人类基因治疗中更安全、更有效。
The first generation of adeno-associated virus (AAV) vectors composed of the naturally occurring capsids and genomes, although effective in some instances, are unlikely to be optimal for gene therapy in humans. The use of the first generation of two different AAV serotype vectors (AAV9 and AAVrh74) in four separate clinical trials failed to be effective in patients with Duchenne muscular dystrophy, although some efficacy was observed in a subset of patients with AAVrh74 vectors leading to US Food and Drug Administration approval (Elevidys). In two trials with the first generation of AAV9 vectors, several serious adverse events were observed, including the death of a patient in one trial, and more recently, in the death of a second patient in an N-of-1 clinical trial. In a fourth trial with the first generation of AAVrh74 vectors, myositis and myocarditis were also observed. Here, we report that capsid- and genome-modified optimized AAVrh74 vectors are significantly more efficient in transducing primary human skeletal muscle cells in vitro and in all major muscle tissues in vivo following systemic administration in a murine model. The availability of optimized AAVrh74 vectors promises to be safe and effective in the potential gene therapy of muscle diseases in humans. The first generation of recombinant adeno-associated virus (AAV) vectors, composed of naturally occurring capsids and genomes, although effective in some instances, are not optimal, given the serious adverse events in and deaths of several patients. Optimized AAV vectors, described here, promise to be safer and more effective in human gene therapy.
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